Recently, many peptide/protein drugs, effective for a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. However, polypeptides or proteins, with their high molecular weight, degradation by gastrointestinal tract enzymes, and short half-life in the body are limited to parenteral administration by such routes as intravenous or intramuscular and subcutaneous injection. Many peptide drugs are of limited solubility and/or stability in conventional liquid carriers and are therefore difficult to formulate and administer. Also, in many cases, numerous administrations are required to get the expected therapeutic effect for an extended period of time. Long-term, controlled delivery of such polypeptides or proteins is essential to provide for the practical application of these medications and to utilize advanced biotechnology derived drugs. Another problem is patient compliance. It is often difficult to get a patient to follow a prescribed dosage regimen, particularly when the prescription is for a chronic disorder and the drug has acute side effects. Therefore, it would be highly desirable to provide a system for the delivery of drugs, polypeptide and protein drugs in particular, at a controlled rate over a sustained period of time without the above mentioned problems in order to optimize the therapeutic efficacy, minimize the side effects and toxicity, and thereby increase the efficacy and increase patient compliance.
Drug loaded polymeric devices and dosage forms have been investigated for long term, therapeutic treatment of different diseases. An important property of the polymer is biodegradability, meaning that the polymer can break down or degrade within the body to nontoxic components either concomitant with the drug release, or, after all the drug has been released. Furthermore, techniques, procedures, solvents and other additives used to fabricate the device and load the drug should result in dosage forms that are safe for the patient, minimize irritation to surrounding tissue, and be a compatible medium for the drug.
Currently, biodegradable implantable controlled release devices are fabricated from solid polymers such as polyglycolic acid, polylactic acid, or copolymers of glycolic and lactic acid. Due to the hydrophobic properties of these polymers, drug loading and device fabrication using these materials requires organic solvents, for example, methylene chloride, chloroform, acetic acid or dimethyl formamide. Due to the toxic nature of some solvents, extensive drying to remove excess solvent is generally required after this process. In most cases the final polymeric device is fabricated in a distinct solid shape (e.g., sphere, slab or rod) requiring an implantation procedure which often results in trauma to tissue.
Currently there are few synthetic or natural polymeric materials which can be used for the controlled delivery of drugs, including peptide and protein drugs, because of the strict regulatory compliance requirements, such as biocompatibility, having a clearly defined degradation pathway, and safety of the degradation products. The most widely investigated and advanced biodegradable polymers in regard to available toxicological and clinical data are the aliphatic poly(.alpha.-hydroxy acids), such as poly(D,L- or L- lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA). These polymers are commercially available and are presently being used as bioresorbable sutures. An FDA-approved system for controlled release of leuprolide acetate, the Lupron Depot.TM., is also based on PLGA copolymers. The Lupron Depot.TM. consists of injectable microspheres, which release leuprolide acetate over a prolonged period (e.g., about 30 days) for the treatment of prostate cancer. Based on this history of use, PLGA copolymers have been the materials of choice in the initial design of parenteral controlled release drug delivery systems using a biodegradable carrier.
Even though there has been some limited success, these polymers have problems associated with their physicochemical properties and methods of fabrication. Hydrophilic macromolecules, such as polypeptides, cannot readily diffuse through hydrophobic matrices or membranes of polylactides. Drug loading and device fabrication using PLA and PLGA often requires toxic organic solvents, and the solid dosage form may mechanically induce tissue irritation.
A. S. Sawhney and J. A. Hubbell, J. Biomed. Mat. Res., 24, 1197-1411 (1990), synthesized terpolymers of D,L-lactide, glycolide and .epsilon.-caprolactone which degrade rapidly in vitro. For example, a terpolymer composition of 60% glycolide, 30% lactide, and 10% .epsilon.-caprolactone exhibited a half-life of 17 days. The hydrophilicity of the material was increased by copolymerization with a poloxamer surfactant (Pluronic F-68).
This poloxamer is a block copolymer comprising about 80% by weight of a relatively hydrophobic poly(oxypropylene) block and 20% by weight of a hydrophilic poly(oxyethylene) block. Copolymerization with the poloxamer resulted in a stronger and partly crystalline material which was mechanically stable at physiological temperatures (e.g. 37.degree. C.) in water. The half-life of this copolymer was slightly increased compared to the base polymer. However, it is known that poloxamer-type surfactants are not biodegradable.
An optimum material for use as an injectable or implantable polymeric drug delivery device should be biodegradable, compatible with hydrophilic or hydrophobic drugs, and allow fabrication with simple, safe solvents, such as water, and not require additional polymerization or other covalent bond forming reactions following administration.
One system, which can be fabricated in aqueous solution is a class of block copolymers referenced above and marketed under the Pluronic.TM. tradename. These copolymers are composed of two different polymer blocks, i.e. hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks to make up a triblock of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene). The triblock copolymers absorb water to form gels which exhibit reverse thermal gelation behavior. However, the Pluronic.TM. system is nonbiodegradable and the gel properties (water soluble gel) and drug release kinetics (very rapid) from those gels have not proven useful and are in need of substantial improvement.
There is a strong need for hydrophilic biodegradable materials which can be used to incorporate water soluble polypeptide drugs in solution. A. S. Sawhney et al., Macromolecules, Vol 26, No. 4, 581-589 (1993) synthesized macromers having a polyethylene glycol central block, extended with oligomers of .alpha.-hydroxy acids such as oligo(D,L-lactic acid) or oligo(glycolic acid) and terminated with acrylate groups. Using nontoxic photoinitiators, these macromers can be rapidly polymerized with visible light. Due to the multifunctionality of the macromers, polymerization results in the formation of crosslinked gels. The gels degrade upon hydrolysis of the oligo(.alpha.-hydroxy acid) regions into polyethylene glycol, the .alpha.-hydroxy acid, and oligo(acrylic acid), and their degradation rates can be tailored by appropriate choice of the oligo(.alpha.-hydroxy acid) from less than 1 day to up to 4 months. However, in this system, an additional component, a photoinitiatoris employed, as well as an additional covalent bond-forming photocrosslinking reaction. Highly variable person-to-person performance would result with this approach due to interperson differences in skin thickness and opacity.
Okada et al., Japanese Patent 2-78629 (1990), synthesized biodegradable block copolymeric materials by transesterification of poly(lactic acid) (PLA) or poly(lactic acid)/glycolic acid (PLGA) and polyethylene glycol (PEG). The molecular weight range for PLGA was 400 to 5,000 and for PEG, 200 to 2,000. The mixture was heated at 100.degree. C. to 250.degree. C. for 1 to 20 hours under a nitrogen atmosphere. The product was miscible with water and formed a hydrogel; however, it precipitated in water above room temperature. In other words, the water solubility and interpolymer chain interactions changed with temperature. This polymer is similar to the polymers described in the Churchill patents discussed below and is utilized as an aqueous suspension or molded into a solid block for implantation. There is no indication that this polymer exhibits properties of reverse thermal gelation and so has to be injected as a solution instead of as a colloidal suspension of polymer.
T. Matsuda, ASAIO Journal, M512-M517 (1993) used a biodegradable polymeric gel to deliver a potent peptidyl antiproliferative agent, angiopeptin, to prevent the myointimal hyperplasia that occurs when a diseased vessel is replaced with an artificial graft or treated by an intravascular device. A highly viscous liquid of a block copolymer composed of poly(lactic acid) and polyethylene glycol (PLA-PEG) block segments was used as an in situ coatable drug carrier. The materials were supplied by Taki Chemical Co., Ltd., Hyogo, Japan. A prolonged slow release of angiopeptin from the polymer gel, consisting of 0.5 g PLA-PEG and 0.5 mg angiopeptin, was observed in vitro over a few weeks when the gel was kept in a buffer solution maintained at 37.degree. C. No early burst release of angiopeptin was observed. Based on these results, the local sustained angiopeptin release from the biodegradable polymeric gel that was coated onto the injured vessel in vivo was theorized to be effective.
L. Martini et al., J. Chem. Soc., Faraday Trans., 90(13), 1961-1966 (1994) synthesized very low molecular weight ABA type triblock copolymers by incorporating hydrophobic poly(.epsilon.-caprolactone), which is known to be subject to degradation in vivo by hydrolytic chain scission involving the ester linkages, and reported the solution properties of the PCL-PEG-PCL block copolymers. Clouding was observed visually when an aqueous solution of the block copolymers was slowly heated. The cloud points of 2 wt % aqueous solutions of the copolymers were 65.degree. C. and 55.degree. C. for PCL-PEG-PCL (450:4000:450) and PCL-PEG-PCL (680:4000:680), respectively. Reversible gelation on cooling of the solutions of PCL-PEG-PCL (680:4000:680) was observed at critical concentrations and temperatures ranging from 13% at 25.degree. C. to 30% at 80.degree. C. No lower gel/sol transition was observed on further cooling the solutions to 0.degree. C. The in vitro degradation rate of PCL-PEG-PCL (680:4000:680) was very slow. Only about a 20% decrease in molar mass (from GPC) was observed over a 16 week period. Such slow degradation is insufficient for a practical drug delivery vehicle.
Churchill et al, U.S. Pat. Nos. 4,526,938 and 4,745,160 show copolymers that are either self-dispersible or can be made self-dispersible in aqueous solutions. These copolymers are ABA triblock or AB block copolymers composed of hydrophobic A-blocks, such as polylactide (PLA) or poly(lactide-co-glycolide)(PLGA), weight of less than 5000 are functional. Furthermore, there is no exemplification of ABA type polymers other than high molecula without the use of organic solvents and hydrophilic B-blocks, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone. Preferably, to be self-dispersible in water without the use of organic solvents, these polymers must contain more than 50% by weight of hydrophilic (B-block) component as compared to hydrophobic (A block) component or, are copolymers where the hydrophobic component (A block) has an average molecular weight of less than 5,000. Although polymers having an average molecular weight as low as 1000 are mentioned, there is no direct teaching of use of such polymers, or that ABA type polymers having a molecular weight polymers having a hydrophobic content of at least 50% by weight. There is no indication that without the use of organic solvents these block copolymers are soluble in aqueous solutions at any temperature, nor is there any indication that drug/polymers can be administered as a solution. Rather, administration is disclosed as a colloidal suspension of the polymer, or, drug/polymer dispersions are freeze dried into a powder and processed by compression molding to form a solid suitable for use as an implantable depot formulation. Aqueous drug/polymer suspensions or dispersions are two phase systems wherein the dispersed polymer phase is suspended in the continuous aqueous phase. Such dispersions are not suitable for use in situations where sterile filtering processes are required to remove bacterial or other toxic particulates, as any such process would also remove the drug/polymer particles and result in sub-therapeutic doses. ABA-type block copolymers that are water soluble and that gel thermally are not included in the Churchill, et al., patents.
From the above discussion it is to be observed that known thermally reversible gels (e.g., Pluronics.TM.) are not inherently useful as drug delivery systems. Although there are block copolymers that possess reverse thermal gelation properties, these gels lack critical characteristics necessary for control of drug release over a sustained period and present toxicity or bio-compatibility issues owing to their non-biodegradability. Thus, while the property of reverse thermal gelation is universally recognized as unique and potentially highly useful in the field of drug delivery, there has yet to be a system developed that possesses the properties necessary for a viable system.